Comparison of the intima‐media thickness of the common carotid artery in patients with rheumatoid arthritis: A single‐center cross‐sectional case‐control study, and a brief review of the literature

Abstract Background and Aim Rheumatoid arthritis (RA) is an autoimmune chronic inflammatory disease affecting 0.5%−1% of adults worldwide. The carotid intima‐media thickness (CIMT) is a simple, reliable, noninvasive marker for subclinical atherosclerosis. The aim of this study was to compare the intima‐media thickness of the common carotid artery in patients with RA with that of healthy patients. Methods In this case‐control study, subjects were recruited from the patients who presented to a private rheumatology clinic. RA was documented by a rheumatologist. All subjects underwent an ultrasound examination of the carotid artery to assess CIMT. Subjects with RA filled out the disease activity score (DAS28) questionnaire. Results Sixty‐two subjects (31 subjects with RA and 31 healthy subjects) took part in the study. The mean age of the subjects in the RA and the control groups was 42.39 ± 12.98 and 44.48 ± 13.56 years, respectively. Values of CIMT were significantly greater in RA subjects compared with their healthy counterparts (p < 0.001). The CIMT increased significantly with increased disease severity (r = 0.73). Subjects were divided into two age groups (≤40 and >40 years). A comparison of CIMT in the mentioned subgroups revealed a remarkable difference in CIMT values between those of the RA patients and those of their control counterparts in both age groups (p = 0.002 and p < 0.001 for those below and above 40 years, respectively). Conclusion CIMT could be used as an efficient clinical index for identifying the early stages of atherosclerosis and predicting cardiovascular events following atherosclerosis in RA patients.

In this cross-sectional case-control study, subjects with RA were selected from among the patients who were referred to a private rheumatology clinic, while the unmatched control group was chosen from the population of non-RA patients who were referred to the clinic.All patients who were older than 16 years were included in the study.Subjects were excluded if they had a body mass index > 30 kg/m 2 , were active smokers, had a positive history of CVD, heart failure, hypertension, or had documented diabetes mellitus or chronic renal failure (glomerular filtration rate <60).A rheumatologist made the diagnosis of RA.Subjects were recruited based on convenience sampling.Before participation, each subject signed written informed consent.The ethical committee of the Azad University of Mashhad approved this study.
The sample size was calculated based on the sample size formula for case-control studies suggested by Kesley et al. with the power of 90 and confidence interval (CI) = 99%. 18The sample size was calculated to hold 18 subjects in each study group.Considering a 20% dropout, the sample size was increased to 22, and assuming a 40% effect size, the final sample size was calculated to consist of 31 subjects in each study group.
All subjects underwent ultrasound scans to assess the CIMT at 5, 10, and 15 mm below the bifurcation of the common carotid with the General Electric (GE) Logiq 500 unit (General Electric Medical Systems) using a 9−7 MHz linear transducer in the supine position and a 45°head tilt.The values of CIMT, peak systolic velocity (PSV), resistance index (RI), pulsatility index (PI), and end-diastolic velocity (EDV) were recorded for all subjects.
Disease severity was assessed in RA patients using the disease activity score 28 (DAS28) questionnaire.This questionnaire comprises eight items, and the score can range from 0 to 10. DAS28 scores below or equal to 3.2 are considered low disease activity, scores between 3.3 and 5.1 are categorized as moderate, and values greater than 5.1 are regarded as severe disease activity. 19

| Statistical analysis
The statistical analysis was conducted apby plying the statistical Sixty-two subjects (36 females and 26 males), consisting of 31 subjects in each group, took part in this study.The mean age of the subjects in the RA and the control groups was 42.39 ± 12.98 and 44.48 ± 13.56 years, respectively.In the RA group, 19 subjects (61.3%) were female, and 12 (38.7%)were male, while in the control group, 17 subjects (54.8%) were female, and 14 (45.2%) were male.
The mean CIMT, PSV, RI, PI, and EDV values in the study groups are shown in Table 1.Except for the latter, the results for all other factors showed a meaningful difference between the two groups.
There was a meaningful difference in CIMT values between the severity categories of RA (p < 0.001) (Table 2).The Spearman's correlation coefficient also revealed a significant relationship between RA severity and CIMT values, showing higher CIMT values with a more severe RA disease activity (r = 0.73, p < 0.05).
The study subjects were divided into two age groups (≤40 and >40 years).As illustrated in Table 3, a comparison of CIMT in the mentioned subgroups revealed a remarkable difference in CIMT values between those of the RA patients and those of their control counterparts in both age groups (p = 0.002 and p < 0.001 for those and above 40 years, respectively).Five (16.13%) of the 31 subjects in the RA group had carotid plaques, while this figure was 4 (12.9%) in the control group.There was no difference in the distribution pattern of carotid plaques between the two groups (χ 2 = 0.13, p = 0.72).

| DISCUSSION
CVD is one of the leading causes of morbidity and mortality in RA patients [20][21][22] It has been shown that the rate of CVD-related mortality in RA patients increases by 50% compared to the general population. 23CIMT can be used as an important factor for future cardiovascular events and as a sign of early atherosclerosis. 23,24is study revealed that, in both the RA and control groups, the CIMT value was higher in those over 40 years of age than in their younger counterparts.This finding was in line with results obtained by Jayakumar et al., who revealed higher CIMT values in Indian RA patients who were between 41 and 55 years old 25 and with results presented in other studies that reported increased CIMT in RA patients with aging 5,26,27 This study also revealed that CIMT increased significantly with increased disease severity in RA.Previous studies have also identified increased CIMT with worsening disease states in RA patients. 5,26ese studies also revealed that the CIMT values increased with the RA duration, a finding not assessed in the current study. 5,26As with our findings regarding disease severity got through the DAS28 questionnaire, another study observed a significant increase in ESR and CRP levels in RA patients with higher CIMT values. 28is study revealed higher CIMT in RA patients in all age groups than the values obtained from the control group.This was in line with the findings of previous research. 1However, not all studies found meaningful differences in CIMT between RA and the control subjects. 26This lack of difference might have been due to including RA patients with mild disease activity.The incidence of atherosclerotic plaques in our RA population was 16.13%, which, however insignificant, was slightly higher than the previously reported figure of 15.6% by Mohan et al. 1 It was previously reported that atherosclerotic plaques were significantly more prevalent in RA patients than amongst the control group. 29ble 4 shows a summary of the results from the other studies.
Considering the observed higher values of CIMT in RA patients compared to those of the controls, this study suggests CIMT assessment as a sensitive marker in assessing the risk of CVD in patients with RA.
It is recommended that further studies with greater sample sizes be performed to assess better the relation between CIMT and CVD risk in RA patients.It is also suggested that disease duration be taken into consideration.
package for social sciences (SPSS) version 21 (IBM Inc.) and Statistica version 10 (StatSoft Inc.).The normality of the variables was assessed using the Shapiro−Wilk test.Mean and standard deviation were used to describe continuous variables.To compare variables between groups, Student's t-test and analysis of variance were applied.All statistical tests were applied two-sided.Frequency and percentage were used to describe categorical values.The χ 2 test was used to compare the distribution pattern of categorical variables between study groups.Using the linear/logistic regression and while controlling for age and gender, we assessed the relationship between CIMT and age.The significance level was considered 0.05, and the CI was considered 0.95.
T A B L E 1 Comparison of study parameters as per study groups.Comparison of CIMT values between study groups as per age categories.Summary of the results from the other studies.